β-Catenin Mediates the Establishment and Drug Resistance of MLL Leukemic Stem Cells

• Published in: Cancer cell 2010-12, Vol.18 (6), p.606-618
• Main Authors: Yeung, Jenny, Esposito, Maria Teresa, Gandillet, Arnaud, Zeisig, Bernd B., Griessinger, Emmanuel, Bonnet, Dominique, So, Chi Wai Eric
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - physiology; Cell Line, Tumor; Drug Resistance, Neoplasm; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Histone-Lysine N-Methyltransferase; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Mice; Mice, Inbred C57BL; Myeloid-Lymphoid Leukemia Protein - physiology; Neoplastic Stem Cells - drug effects; Wnt Proteins - physiology
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2010.10.032

Identification of molecular pathways essential for cancer stem cells is critical for understanding the underlying biology and designing effective cancer therapeutics. Here, we demonstrated that β-catenin was activated during development of MLL leukemic stem cells (LSCs). Suppression of β-catenin reversed LSCs to a pre-LSC-like stage and significantly reduced the growth of human MLL leukemic cells. Conditional deletion of β-catenin completely abolished the oncogenic potential of MLL-transformed cells. In addition, established MLL LSCs that have acquired resistance against GSK3 inhibitors could be resensitized by suppression of β-catenin expression. These results unveil previously unrecognized multifaceted functions of β-catenin in the establishment and drug-resistant properties of MLL stem cells, highlighting it as a potential therapeutic target for an important subset of AMLs. ► Differential activation of Wnt/β-catenin pathway is required for MLL LSC development ► Suppression of β-catenin reverses MLL LSCs to a pre-LSC like stage ► Down modulation of β-catenin impedes human AML proliferation ► Suppression of β-catenin sensitizes MLL LSCs to GSK3 inhibitors